Markers of Favorable Response to FcRn Inhibitors(INFORM)

Overview

Myasthenia gravis is an autoimmune neurological disease caused by autoantibodies primarily directed against components of the postsynaptic membrane of the neuromuscular junction. Approximately 85% of patients have antibodies directed against the acetylcholine receptor (anti-AChR). Anti-AChR antibodies act through three distinct mechanisms: 1. Activation of the classical complement pathway: Formation of membrane-attack complexes (MACs) results in the destruction of the postsynaptic membrane. 2. Mechanical blockade: Anti-AChR antibodies block the acetylcholine binding site on its receptor. 3. Internalization and lysosomal degradation: Bivalent IgG causes cross-linking of adjacent receptors leading to internalization and degradation of AChRs (antigenic modulation). Patient mortality has significantly reduced due to effective treatments preventing severe exacerbations of myasthenic symptoms. In the past five years, the FDA and EMA have approved complement inhibitors and FcRn inhibitors for treating generalized myasthenia gravis with anti-AChR antibodies. Many other therapies are currently in phase 3 clinical trials or under regulatory review. However, there is no specific evidence to support which patients benefit most from one treatment class over another. Given their relative efficacy compared to conventional therapies and high costs, their future role in the therapeutic arsenal is unclear. A personalized approach considering the different pathogenic mechanisms of anti-AChR and single gene polymorphisms involved in treatment response is essential for effective therapeutic choice. In July 2023, AIFA approved the reimbursement of Efgartigimod in Italy for treating adult patients with generalized myasthenia gravis with anti-AChR antibodies, in addition to standard therapy. FcRn inhibitors (including Efgartigimod) prevent the interaction of IgG with the neonatal Fc receptor for immunoglobulin fragments, reducing IgG recycling and promoting the degradation of IgG and pathogenic antibodies without affecting albumin levels. There is heterogeneity among patients in their response to FcRn inhibitors therapies. Currently, there is no specific evidence indicating which patients may benefit most from this class of treatments. Interindividual heterogeneity in the autoantibody repertoire, predominance of different pathogenic mechanisms, and single gene polymorphisms affecting treatment response. Investigating the immune profile and specific gene polymorphisms in myasthenic patients needing these innovative therapies could identify predictive biomarkers and personalize therapeutic choices.